PHASE-I AND PHARMACOLOGICAL STUDY OF INTRAARTERIAL HEPATIC ADMINISTRATION OF PIRARUBICIN IN PATIENTS WITH ADVANCED HEPATIC METASTASES

Intra-arterial hepatic (i.a.h.) administration of the doxorubicin anal ogue pirarubicin was evaluated in a phase I trial, based on preclinica l studies that showed an advantage of pirarubicin over doxorubicin aft er locoregional hepatic administration. Pirarubicin was given to 9 pat ients with metastatic liver disease with intrapatient dose escalation. Of the 58 cycles evaluable for tolerance, no hepatobiliary or vascula r toxicity was observed. The dose-limiting toxicity was granulocytopen ia: the maximum administered doses ranged from 50 to 120 mg/m(2), sugg esting variable rates of pirarubicin hepatic extraction between patien ts. Pharmacokinetic data obtained in 7 patients, in which a direct com parison of intravenous (i.v.) and i.a.h. administration was possible, indicated a median i.v./i.a.h. ratio of 7.4 for the maximal plasma con centration, and a median ratio of 4 for the area under the plasma conc entrations versus time curves, suggesting a high pirarubicin hepatic e xtraction. An unexpectedly high response rate was observed: two comple te (colorectal carcinoma) and two partial responses. These data demons trate that i.a.h. pirarubicin not only produced high locoregional conc entrations and reduced systemic exposure, but can also achieve respons es in metastatic liver disease of colorectal origin.